EP4180060A1 - Feste zusammensetzungen mit einem peptid oder einem protein und einer acylierten aminosäure - Google Patents

Feste zusammensetzungen mit einem peptid oder einem protein und einer acylierten aminosäure Download PDF

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Publication number
EP4180060A1
EP4180060A1 EP21208347.1A EP21208347A EP4180060A1 EP 4180060 A1 EP4180060 A1 EP 4180060A1 EP 21208347 A EP21208347 A EP 21208347A EP 4180060 A1 EP4180060 A1 EP 4180060A1
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EP
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Prior art keywords
peptide
protein
group
composition
composition comprises
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English (en)
French (fr)
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Adocia SAS
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Adocia SAS
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Priority to EP21208347.1A priority Critical patent/EP4180060A1/de
Priority to EP22818291.1A priority patent/EP4433093A1/de
Priority to PCT/EP2022/082013 priority patent/WO2023084118A1/en
Publication of EP4180060A1 publication Critical patent/EP4180060A1/de
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/605—Glucagons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • compositions comprising a peptide and a permeation enhancer, said permeation enhancer being an acylated aminoacid, also called AC-aa, their method of preparation and their use in medicine.
  • the peptides or proteins which are marketed under oral form are mostly small cyclic non-acylated or non-pegylated peptides.
  • small is meant a molecular weight of less or equal to 1200 Da.
  • WO2014060512A1 which has data on "short" fatty acid teaches that the strongest effect is observed for FA-aa's with longer fatty acid chains (Example 12) and that the FA-aa with a fatty acid chain having 8 to 10 carbon atoms have a very modest, if any effect on the transport of Growth Hormones compounds (Example 20).
  • the table M from Example 20 shows that a composition comprising the active principle and a FA-aa with a fatty acid chain comprising 8 carbon atoms has almost no effect on delivery of the active principle, as the fold increase of delivery compared to a composition comprising the active principle alone is around 0.6 to 1.2.
  • the invention proposes a way to solve at least part of the above cited problems.
  • composition according to the invention relates to a solid composition comprising a peptide or a protein and an acylated aminoacid AC-aa, or a salt thereof, wherein the acyl group AC comprises from 4 to 8 carbon atoms.
  • the acyl group (C(O)-Ri) also called AC comprises from 4 to 8 carbon atoms and said composition comprises at least 300 mg/g of AC-aa relative to the total weight of the composition.
  • the composition comprises at least 400 mg/g of AC-aa relative to the total weight of the composition.
  • the composition comprises at least 500 mg/g of AC-aa relative to the total weight of the composition.
  • composition according to the invention relates to a solid composition comprising a peptide or a protein and an acylated aminoacid, also called AC-aa, or a salt thereof, wherein the acyl group comprises from 4 to 8 carbon atoms.
  • composition according to the invention relates to a solid composition
  • a solid composition comprising a peptide or a protein, an acylated aminoacid, also called AC-aa, or a salt thereof, wherein the acyl group comprises from 4 to 8 carbon atoms and a lubricant.
  • composition according to the invention relates to a solid composition
  • a solid composition comprising a peptide or a protein, an acylated aminoacid, also called AC-aa, or a salt thereof, wherein the acyl group comprises from 4 to 8 carbon atoms and a pH modifier.
  • the invention also relates to a unitary solid dosage comprising or consisting of the composition of the invention.
  • the unitary solid dosage comprises a peptide or a protein and at least 300 mg/g of acylated aminoacid, also called AC-aa, or a salt thereof, wherein the acyl group AC comprises from 4 to 8 carbon atoms.
  • the invention also relates to a unitary solid dosage comprising a peptide or a protein and at least 300 mg/g of acylated aminoacid, also called AC-aa, or a salt thereof, wherein the acyl group AC comprises from 4 to 8 carbon atoms, said unitary solid dosage comprising at least 50 mg of AC-aa.
  • the invention also relates to a pharmaceutical formulation comprising a solid composition as disclosed in this specification.
  • the invention also relates to a solid composition for oral delivery comprising a peptide or a protein and an acylated aminoacid, also called AC-aa, or a salt thereof, wherein the acyl group comprises from 4 to 8 carbon atoms.
  • the invention also relates to a method of treatment comprising the step of orally taking a solid composition as disclosed in the specification for preventing or treating a disease.
  • AC-aa is a permeation enhancer
  • the composition is an oral composition.
  • the AC-aa are also abbreviated like Cation-Trigram or Quadrigram of the aa-number of carbon of the acyl.
  • NaPheC8 sodium salt of N-octanoyl phenylalanine
  • NaPGlyC6 sodium salt of N-hexanoyl phenylglycine
  • peptides is meant amides derived from two or more amino carboxylic acid molecules (the same or different) by formation of a covalent bond from the carbonyl carbon of one to the nitrogen atom of another with formal loss of water.
  • the term is usually applied to structures formed from ⁇ -amino acids, but it includes those derived from any amino carboxylic acid. This definition comes from IUPAC gold book (https://goldbook.iupac.org/terms/view/P04479).
  • polypeptides is meant peptides containing ten or more amino acid residues. Polypeptides are specific type of peptides.
  • peptides and “polypeptides” have a molecular weight of less than or equal to 10 000.
  • proteins is meant naturally occurring or synthetic polypeptides having molecular weight greater than about 10 000. This definition comes from IUPAC gold book.
  • amino acid » comprises the amino acids encoded by the genetic code and amino acids not coded by the genetic code and synthetic amino acids.
  • gamma-carboxyglutamate hydroxyproline (Hyp), ornithine (Orn), sarcosine (Sarc) and phosphoserine.
  • alpha-aminoisobutyric acid (Aib), alpha-aminobutyric acid (Abu), tert-butyl-glycine, beta-alanine, 3-aminomethyl benzoic acid, anthranilic acid and phenyglycine (PGly).
  • acylated aminoacid AC-aa is meant a compound obtained by acylation of an amino acid with an acid, and -aa is issued from an aminoacid and AC is issued from an acid.
  • the aa is issued from a L-aminoacid.
  • L-aminoacid is meant that the enantiomeric excess is at least 50%, in particular at least 75%, more specifically at least 90%, or even more specifically more than 95%.
  • the aa is issued from a racemic mixture.
  • the aa of AC-aa is issued from a non cationic amino acid, a non polar hydrophobic amino acid, a polar non charged amino acid or a polar acidic amino acid.
  • the aa of AC-aa is issued from a non cationic amino acid, selected from the group consisting of Alanine (Ala), Valine (Val), Leucine (Leu), Isoleucine (Ile), Phenylalanine (Phe), Phenylglycine (PGly), Tryptophane (Trp), Methionine (Met), Proline (Pro), Sarcosine (Sarc), Serine (Ser), Threonine (Thr), Cysteine (Cys), Tyrosine (Tyr), Asparagine (Asn), Glutamine (Gin), Aspartic acid (Asp) and Glutamic acid (Glu).
  • a non cationic amino acid selected from the group consisting of Alanine (Ala), Valine (Val), Leucine (Leu), Isoleucine (Ile), Phenylalanine (Phe), Phenylglycine (PGly), Tryptophane (Trp), Methionine (Met), Proline (Pro),
  • the aa of AC-aa is issued from a non polar hydrophobic amino acid selected from the group consisting of Alanine (Ala), Valine (Val), Leucine (Leu), Isoleucine (Ile), Phenylalanine (Phe), Phenylglycine (PGly), Tryptophane (Trp), Methionine (Met), Proline (Pro) and Sarcosine (Sarc).
  • a non polar hydrophobic amino acid selected from the group consisting of Alanine (Ala), Valine (Val), Leucine (Leu), Isoleucine (Ile), Phenylalanine (Phe), Phenylglycine (PGly), Tryptophane (Trp), Methionine (Met), Proline (Pro) and Sarcosine (Sarc).
  • the aa of AC-aa is issued from a polar non-charged amino acid selected from the group consisting of Serine (Ser), Threonine (Thr), Cysteine (Cys), Tyrosine (Tyr), Asparagine (Asn), and Glutamine (Gin).
  • the aa of AC-aa is issued from an aromatic amino acid selected from the group consisting of Phenylalanine (Phe), Phenylglycine (PGly), Tryptophane (Trp) and Tyrosine (Tyr).
  • the aa of AC-aa is issued from a polar acidic amino acid selected from the group consisting of Aspartic acid (Asp) and Glutamic acid (Glu).
  • the aa of AC-aa is issued from an aliphatic amino acid selected from the group consisting of Alanine (Ala), Valine (Val), Leucine (Leu) and Isoleucine (lie).
  • the aa of AC-aa is issued from of an aminoacid in the form of the L-isomer, the D-isomer or a mixture of enantiomers.
  • the AC group comprises from 4 to 8 carbon atoms.
  • the AC group comprises from 6 to 8 carbon atoms.
  • the AC group comprises 8 carbon atoms.
  • the AC group comprises 6 carbon atoms.
  • the -R 1 group of the acyl group (-C(O)-Ri) is an aliphatic chain comprising from 3 to 7 carbon atoms.
  • the -R1 group of the acyl group (-C(O)-Ri) is an alkyl group comprising from 5 to 7 carbon atoms.
  • the -R 1 group of the acyl group (-C(O)-Ri) is an aliphatic chain comprising from 7 carbon atoms.
  • the -R1 group of the acyl group (-C(O)-Ri) is an alkyl group comprising from 5 carbon atoms.
  • the alkyl group of the AC is a linear alkyl group.
  • the AC group is issued from an acid chosen from octanoic acid, hexanoic acid or butanoic acid.
  • the AC group is issued from octanoic acid.
  • the AC group is issued from hexanoic acid.
  • the AC group is issued from butanoic acid.
  • the AC-aa is a salt of AC-aa wherein the cationic part is chosen from the group consisting of Na + and K + .
  • the cationic part is Na + .
  • the cationic part is K + .
  • AC-aa is chosen amongst the AC-aa wherein -aa is an alpha amino acid and has the general Formula I : wherein :
  • -R1 comprises from 3 to 7 carbon atoms.
  • -R1 comprises from 5 to 7 carbon atoms.
  • -R1 comprises 7 carbon atoms.
  • -R1 comprises 5 carbon atoms.
  • -R1 is a linear alkyl group.
  • AC-aa is selected from N-butanoyl-Alanine, N-butanoyl-Valine, N-butanoyl-Leucine, N-butanoyl-Isoleucine, N-butanoyl-Phenylalanine, N-butanoyl-Phenylglycine, N-butanoyl-Tryptophane, N-butanoyl-Methionine, N-butanoyl-Proline, N-butanoyl-Sarcosine, N-butanoyl-Serine, N-butanoyl-Threonine, N-butanoyl-Cysteine, N-butanoyl-Tyrosine, N-butanoyl-Asparagine, N-butanoyl-Glutamine, N-butanoyl-Aspartic acid and N-butanoyl-Glutamic acid.
  • AC-aa is selected from the group consisting of N-butanoyl-Alanine, N-butanoyl-Valine, N-butanoyl-Leucine, N-butanoyl-Isoleucine, N-butanoyl-Phenylalanine, N-butanoyl-Phenylglycine N-butanoyl-Tryptophane, N-butanoyl-Methionine, N-butanoyl-Proline, N-butanoyl-Sarcosine.
  • AC-aa is selected from the group consisting of N-butanoyl-Serine, N-butanoyl-Threonine, N-butanoyl-Cysteine, N-butanoyl-Tyrosine, N-butanoyl-Asparagine and N-butanoyl-Glutamine.
  • AC-aa is selected from the group consisting of N-butanoyl-Aspartic acid and N-butanoyl-Glutamic acid.
  • AC-aa is selected from the group consisting of N-butanoyl-Phenylalanine, N-butanoyl-Phenylglycine, N-butanoyl-Tryptophane and N-butanoyl-Tyrosine.
  • AC-aa is selected from the group consisting of N-hexanoyl-Alanine, N-hexanoyl-Valine, N-hexanoyl-Leucine, N-hexanoyl-Isoleucine, N-hexanoyl-Phenylalanine, N-hexanoyl-Phenylglycine, N-hexanoyl-Tryptophane, N-hexanoyl-Methionine, N-hexanoyl-Proline, N-hexanoyl-Sarcosine, N-hexanoyl-Serine, N-hexanoyl-Threonine, N-hexanoyl-Cysteine, N-hexanoyl-Tyrosine, N-hexanoyl-Asparagine, N-hexanoyl-Glutamine, N-hexanoyl-Aspartic
  • AC-aa is selected from the group consisting of N-hexanoyl-Alanine, N-hexanoyl-Valine, N-hexanoyl-Leucine, N-hexanoyl-Isoleucine, N-hexanoyl-Phenylalanine, N-hexanoyl-Phenylglycine N-hexanoyl-Tryptophane, N-hexanoyl-Methionine, N-hexanoyl-Proline and N-hexanoyl-Sarcosine.
  • AC-aa is selected from the group consisting of N-hexanoyl-Serine, N-hexanoyl-Threonine, N-hexanoyl-Cysteine, N-hexanoyl-Tyrosine, N-hexanoyl-Asparagine and N-hexanoyl-Glutamine.
  • AC-aa is selected from the group consisting of N-hexanoyl-Aspartic acid and N-hexanoyl-Glutamic acid.
  • AC-aa is selected from the group consisting of N-hexanoyl-Phenylalanine, N-hexanoyl-Phenylglycine N-hexanoyl-Tryptophane and N-hexanoyl-Tyrosine.
  • AC-aa is selected from the group consisting N-octanoyl-Alanine, N-octanoyl-Valine, N-octanoyl-Leucine, N-octanoyl-Isoleucine, N-octanoyl-Phenylalanine, N-octanoyl-Phenylglycine, N-octanoyl-Tryptophane, N-octanoyl-Methionine, N-octanoyl-Proline, N-octanoyl-Sarcosine, N-octanoyl-Serine, N-octanoyl-Threonine, N-octanoyl-Cysteine, N-octanoyl-Tyrosine, N-octanoyl-Asparagine, N-octanoyl-Glut
  • AC-aa is selected from the group consisting of N-octanoyl-Alanine, N-octanoyl-Valine, N-octanoyl-Leucine, N-octanoyl-Isoleucine, N-octanoyl-Phenylalanine, N-octanoyl-Phenylglycine, N-octanoyl-Tryptophane, N-octanoyl-Methionine, N-octanoyl-Proline and N-octanoyl-Sarcosine.
  • AC-aa is selected from the group consisting of N-octanoyl-Serine, N-octanoyl-Threonine, N-octanoyl-Cysteine, N-octanoyl-Tyrosine, N-octanoyl-Asparagine and N-octanoyl-Glutamine.
  • AC-aa is selected from the group consisting of N-octanoyl-Aspartic acid and N-octanoyl-Glutamic acid.
  • AC-aa is selected from the group consisting of N-octanoyl-Phenylalanine, N-octanoyl-Phenylglycine, N-octanoyl-Tryptophane and N-octanoyl-Tyrosine.
  • N-acyl-aa means either the acid form, or its salt form, in particular its sodium or potassium salt form.
  • AC-aa has a critical micellar concentration in solution in water in biorelevant's FASSIF buffer at pH 6.5 and 25°C, also called CMC, of at least 1 mM.
  • the AC-aa has a CMC of at least 2.5 mM.
  • the AC-aa has a CMC of at least 5 mM.
  • the AC-aa has a CMC of at least 10 mM.
  • the AC-aa has a CMC of at least 15 mM.
  • the AC-aa has a CMC of at least 20 mM.
  • the AC-aa has a CMC of at least 25 mM.
  • the AC-aa has a CMC of at least 30 mM.
  • the AC-aa has a CMC of at most 200 mM.
  • the composition comprises at least 300 mg/g of AC-aa relative to the total weight of the composition.
  • the composition comprises at least 400 mg/g of AC-aa relative to the total weight of the composition.
  • the composition comprises at least 500 mg/g of AC-aa relative to the total weight of the composition.
  • the composition comprises at least 600 mg/g of AC-aa relative to the total weight of the composition.
  • the composition comprises at least 700 mg/g of AC-aa relative to the total weight of the composition.
  • the composition comprises at least 800 mg/g of AC-aa relative to the total weight of the composition.
  • the composition comprises at least 900 mg/g of AC-aa relative to the total weight of the composition.
  • the composition comprises at most 980 mg/g of AC-aa relative to the total weight of the composition.
  • the composition comprises at most 950 mg/g of AC-aa relative to the total weight of the composition.
  • the composition comprises at most 900 mg/g of AC-aa relative to the total weight of the composition.
  • the composition comprises at most 800 mg/g of AC-aa relative to the total weight of the composition.
  • composition according to the invention comprises at least one further permeation enhancer in addition to AC-aa.
  • the further permeation enhancer is chosen from the group consisting of caprate, in particular sodium caprate, caprylate, in particular sodium caprylate, bile salts, salcaprozate, in particular sodium salcaprozate (SNAC).
  • the further permeation enhancer is chosen from the group consisting of caprate, in particular sodium caprate, caprylate, in particular sodium caprylate.
  • the further permeation enhancer is chosen from the group consisting of caprate, in particular sodium caprate.
  • the composition comprises at least 300 mg/g of permeation enhancers relative to the total weight of the composition.
  • the composition comprises at least 400 mg/g of permeation enhancers relative to the total weight of the composition.
  • the composition comprises at least 500 mg/g of permeation enhancers to the total weight of the composition.
  • the composition comprises at least 600 mg/g of permeation enhancers relative to the total weight of the composition.
  • the composition comprises at least 700 mg/g of permeation enhancers relative to the total weight of the composition.
  • the composition comprises at least 800 mg/g of permeation enhancers relative to the total weight of the composition.
  • the composition comprises at least 900 mg/g of permeation enhancers relative to the total weight of the composition.
  • the composition comprises at most 990 mg/g of permeation enhancers relative to the total weight of the composition.
  • the composition comprises at most 980 mg/g of permeation enhancers relative to the total weight of the composition.
  • the composition comprises at most 950 mg/g of permeation enhancers relative to the total weight of the composition.
  • the composition comprises at most 900 mg/g of permeation enhancers relative to the total weight of the composition.
  • the composition comprises at most 800 mg/g of permeation enhancers relative to the total weight of the composition.
  • the peptide or protein is a therapeutic peptide or protein.
  • the peptide or protein is long acting.
  • long acting » is meant having a half life in plasma of at least 1 day.
  • long acting peptide or protein have a half life in plasma of at least 2 days.
  • long acting peptide or protein have a half life in plasma of at least 3 days.
  • long acting peptide or protein have a half life in plasma of at least 5 days.
  • long acting peptide or protein have a half life in plasma of at least 7 days.
  • long acting peptide or protein have a half life in plasma of at least 10 days.
  • long acting peptide or protein have a half life in plasma of at least 15 days.
  • the peptide or protein is short acting.
  • short acting » is meant having a half life in plasma of less than 1 day.
  • short acting peptide or protein have a half life in plasma of at most 18 hours.
  • short acting peptide or protein have a half life in plasma of at most 12 hours.
  • short acting peptide or protein have a half life in plasma of at most 6 hours.
  • short acting peptide or protein have a half life in plasma of at most 4 hours.
  • short acting peptide or protein have a half life in plasma of at most 2 hours.
  • the peptide or protein has a solubility in water at 25°C or more of at least 10 mg/ml.
  • the peptide or protein has a solubility in water at 25°C or more of at least 20 mg/ml.
  • the peptide or protein has a solubility in water at 25°C or more of at least 30 mg/ml.
  • the peptide or protein has a solubility in water at 25°C or more of at least 40 mg/ml.
  • the peptide or protein has a solubility in water at 25°C or more of at least 50 mg/ml.
  • the peptide or protein has a solubility in water at 25°C or more of at most 40 mg/ml.
  • the peptide or protein has a solubility in water at 25°C or more of at most 30 mg/ml.
  • the peptide or protein has a solubility in water at 25°C or more of at most 20 mg/ml.
  • the peptide or protein has a solubility in water at 25°C or more of at most 10 mg/ml.
  • the peptide or protein has a molecular weight of at least 1500 Da.
  • the peptide or protein has a molecular weight of at least 2000 Da.
  • the peptide or protein has a molecular weight of at least 2500 Da.
  • the peptide or protein has a molecular weight of at least 3000 Da.
  • the peptide or protein has a molecular weight of at least 3500 Da.
  • the peptide or protein has a molecular weight of at least 4000 Da.
  • the peptide or protein has a molecular weight of at most 20000 Da.
  • the peptide or protein has a molecular weight of at most 15000 Da.
  • the peptide or protein has a molecular weight of at most 10000 Da.
  • the peptide or protein has a molecular weight of at most 5000 Da.
  • the composition comprises from 0.25 to 20 wt% of peptide or protein.
  • the composition comprises from 0.5 to 20 wt% of peptide or protein.
  • the composition comprises from 1 to 20 wt% of peptide or protein.
  • the composition comprises from 2 to 20 wt% of peptide or protein.
  • the composition comprises from 5 to 20 wt% of peptide or protein.
  • the composition comprises from 1 to 15 wt% of peptide or protein.
  • the composition comprises from 2 to 15 wt% of peptide or protein.
  • the composition comprises from 5 to 15 wt% of peptide or protein.
  • the peptide or protein is chosen from the group consisting of GLP-1 RA, GLP-2 RA, insulin and insulin analogs, amylin RA, GIP RA, PYY RA, dual agonists GIP/GLP-1, dual agonists GLP-1/glucagon, ParaThyroid Hormones (PTH) and PTH analogs, InterLeukines (IL) and IL analogs, Growth Hormones (GH) and GH analogs, Insulin Growth Factors (IGF) and IGF analogs, Interferons (IFN) and IFN analogs.
  • GLP-1 RA GLP-2 RA
  • insulin and insulin analogs amylin RA
  • GIP RA GIP RA
  • PYY RA dual agonists GIP/GLP-1
  • GLP-1/glucagon ParaThyroid Hormones
  • PTH ParaThyroid Hormones
  • IL InterLeukines
  • GH Growth Hormones
  • IGF Insulin Growth Factors
  • the peptide or protein is a GLP-1 RA chosen from the group consisting of semaglutide.
  • the peptide or protein is a GLP-2 RA chosen from the group consisting of dulaglutide.
  • the peptide or protein is insulin or an insulin analog.
  • the insulin analog is chosen from the group consisting of degludec and detemir.
  • the peptide or protein is an amylin RA or an amylin analog chosen from the group consisting of pramlintide.
  • the peptide or protein is a GIP RA chosen from the group consisting of GIP RA disclosed in WO2021021877 , WO16066744 and WO2018181864 .
  • the peptide or protein is a PYY RA chosen from the group consisting of PYY (1-36), PYY (3-36) and PYY RA disclosed in WO2021023817 , WO19147650 and WO2016198682 .
  • the peptide or protein is a dual agonist GIP/GLP-1 chosen from the group consisting of dual agonist GIP/GLP-1 disclosed in WO2016111971 , and in particular Tirzepatide.
  • the peptide or protein is a dual agonists GLP-1/glucagon.
  • the peptide or protein is an analog of oxyntomodulin.
  • the peptide or protein is a ParaThyroid Hormone (PTH) or a PTH analog chosen from the group consisting of human PTH and PTH analogs.
  • PTH ParaThyroid Hormone
  • the peptide or protein is an InterLeukines (IL) or IL analog chosen from the group consisting of IL-11 and analogs.
  • IL InterLeukines
  • the peptide or protein is a Growth Hormone (GH) or a GH analog chosen from the group consisting of Human Growth Hormone and analogs, in particular human growth hormone bearing an acylated graft.
  • GH Growth Hormone
  • analogs chosen from the group consisting of Human Growth Hormone and analogs, in particular human growth hormone bearing an acylated graft.
  • the peptide or protein is an Insulin Growth Factor (IGF) or an IGF analog chosen from the group consisting of IGF-1.
  • IGF Insulin Growth Factor
  • the peptide or protein is an Interferon (IFN) or an IFN analog chosen from the group consisting of INF beta-la, INF beta-1b and INF gamma.
  • IFN Interferon
  • IFN analog chosen from the group consisting of INF beta-la, INF beta-1b and INF gamma.
  • the peptide or protein is a peptide or protein comprising modifications in the form of a covalent modification such as a side chain attached to one or more amino acids of the hydrophylic peptide or protein.
  • the peptide or protein is a peptide or protein comprising modifications in the form of an attachment of amides, carbohydrates, alkyl groups, acyl groups, esters, PEGylations and the like.
  • the peptide or protein is a peptide or protein comprising modifications in the form of an attachment at least one acyl group, said acyl group comprising at least 10 carbon atoms.
  • the acyl moiety is -OEG-OEG-gamma-L-Glu-octadecanedioyl, wherein OEG is -COCH 2 O(CH 2 ) 2 O(CH 2 ) 2 NH-
  • the peptide or protein is a peptide or protein comprising modifications in the form of an attachment at least one PEGylation.
  • composition does not comprise Growth Hormone. In a specific embodiment, the composition does not comprise growth hormones such as disclosed in WO2014060512 .
  • composition does not comprise human Growth Hormone.
  • composition does not comprise insulin.
  • composition does not comprise long-acting insulin.
  • composition does not comprise a long-acting insulin, in particular such as disclosed in WO2005012347 , WO2009063072 and WO9507931 .
  • the composition does not comprise peptide or protein, in particular insulins, such as disclosed in WO2012140155 and WO2014060447 .
  • composition does not comprise insulin comprising an acylated graft.
  • the weight ratio AC-aa / peptide or protein is going from 1:1 to 200:1.
  • the weight ratio AC-aa / peptide or protein is going from 1:1 to 100:1.
  • the weight ratio AC-aa / peptide or protein is going from 1:1 to 50:1.
  • the weight ratio AC-aa / peptide or protein is going from 2:1 to 40:1.
  • the weight ratio AC-aa / peptide or protein is going from 4:1 to 30:1.
  • the weight ratio AC-aa / peptide or protein is going from 6:1 to 20:1.
  • the composition comprises less than 10 % w/w of water.
  • the composition comprises less than 5 % w/w of water.
  • the composition comprises less than 2 % w/w of water.
  • the composition comprises less than 1 % w/w of water.
  • the solid composition comprises a mixture of particles comprising the AC-aa and particles comprising the peptide or protein.
  • the AC-aa and the peptide or protein are present in the composition in the ratio and percentages as disclosed above.
  • the solid composition consists of a mixture of particles comprising AC-aa and of particles comprising the peptide or protein.
  • the AC-aa and the peptide or protein are present in the composition in the ratio and percentages as disclosed above.
  • the solid composition consists of particles wherein the AC-aa and the peptide or protein are mixed. In particular in the ratio and percentages as disclosed above.
  • the particles comprising at the same time peptide or protein and AC-aa may be obtained via lyophilization, freeze drying, spray drying, wet granulation or dry granulation.
  • these particles are free from each other.
  • these particles are held together.
  • the composition comprises excipients chosen from the list consisting of lubricants, surfactants, pH modifiers, disintegrants, binders, fillers, glidants, diluents and preservatives.
  • the composition comprises only excipients chosen from the list consisting of lubricants, surfactants, pH modifiers, disintegrants, binders, fillers, glidants, diluents and preservatives.
  • the composition comprises only excipients chosen from the list consisting of lubricants, pH modifiers.
  • the composition comprises at most 20 % w/w of excipients, in particular of excipients such as listed above.
  • the composition comprises at most 15 % w/w of excipients, in particular of excipients such as listed above.
  • the total amount of binder, filler and glidant is at most 10 % w/w of the composition.
  • the composition comprises at least one pH modifier.
  • the pH modifier can be chosen from the group consisting of sodium carbonate, which formula is Na 2 CO 3 , phosphates, citrates, citric acid, tartarate and tartaric acid.
  • Citrates can be monosodium citrate, disodium citrate and/or trisodium citrate. In particular it can be trisodium citrate.
  • Tartarate can be monosodium and/or disodium tartarate. In particular this is monosodium tartarate.
  • the pH modifier is sodium carbonate, which formula is Na 2 CO 3 .
  • composition comprises at least 1 % w/w of pH modifier.
  • composition comprises at least 2 % w/w of pH modifier.
  • composition comprises at least 5 % w/w of pH modifier.
  • composition comprises at most 15 % w/w of pH modifier.
  • composition comprises at most 10 % w/w of pH modifier.
  • composition comprises at most 8 % w/w of pH modifier.
  • the composition comprises at least one lubricant.
  • the lubricant is chosen from the group consisting of magnesium stearate or glyceryl dibehenate.
  • the lubricant is magnesium stearate.
  • the lubricant is glyceryl dibehenate.
  • composition comprises more than or is equal to 0.1 % w/w of lubricant.
  • composition comprises more than or is equal to 0.2 % w/w of lubricant.
  • composition comprises more than or is equal to 0.5 % w/w of lubricant.
  • composition comprises less than 5 % w/w of lubricant.
  • composition comprises less than 3 % w/w of lubricant.
  • composition comprises less than 2.5 % w/w of lubricant.
  • the composition comprises less than 2 % w/w of lubricant.
  • composition comprises less than 1 % w/w of lubricant.
  • composition comprises between 0.25 and 2.5 % w/w of lubricant.
  • the composition is in the form of a unitary solid dosage form, such as capsules, tablets, dragees, pills, lozenges, powders, and granules.
  • the composition is in the form of a unitary solid dosage form, such as capsules, tablets, dragees, pills, lozenges, powders, and granules, said unitary dosage form comprising at least 50 mg of AC-aa.
  • the unitary solid dosage form is under the form of a capsule.
  • the unitary solid dosage form is under the form of a hard capsule.
  • the unitary solid dosage form is under the form of a soft capsule.
  • the capsules may contain powders, granules, crushed tablets that contains the peptide or a protein and one or more inert ingredients. Capsules can be formulated with delayed release characteristics.
  • composition is encapsulated or the like to allow the composition which is swallowed to be in contact with the gastro intestinal system.
  • the encapsulation allows the composition to be delivered in the stomach.
  • composition may be in the form of a film coated tablets with a thin layer of water soluble material that dissolves rapidly in the stomach.
  • the encapsulation allows the composition to be delivered in the intestines.
  • composition may be encapsulated with an enteric coating.
  • This enteric coating may be in the form of a polymer coating or of a polymer capsule that controls disintegration and release of the composition.
  • the enteric coating may be soft technology. In an embodiment it is soft capsule technnology.
  • the enteric coating may be hard technology. In an embodiment it is hard capsule technnology.
  • enteric coating means a coating that controls disintegration and release of the oral dosage form.
  • the site of disintegration and release of the solid dosage form may be designed depending on the pH of the targeted area, where absorption of the peptide or protein is desired, thus also includes acid resistant protective coatings.
  • the composition is for use as a medicament.
  • the composition is for preventing or treating obesity, Diabetes Type 1, Diabetes Type 2, NASH, thrombocytopaenia, Short Bowel Syndrom (SBS), adult GH deficiency, GH disorders, Short stature syndrome, Turner's syndrome, Achondroplasia, Prader-Willi syndrome, Short stature in children, osteoporosis and hypoparathyroidism, Multiple sclerosis, Bone disorders.
  • SBS Short Bowel Syndrom
  • composition is for preventing or treating obesity.
  • composition is for preventing or treating Diabetes Type 1.
  • composition is for preventing or treating Diabetes Type 2.
  • composition is for preventing or treating NASH.
  • composition is for preventing or treating thrombocytopaenia.
  • composition is for preventing or treating Short Bowel Syndrom (SBS).
  • SBS Short Bowel Syndrom
  • composition is for preventing or treating adult GH deficiency, GH disorders, Short stature syndrome, Turner's syndrome, Achondroplasia, Prader-Willi syndrome or Short stature in children.
  • composition is for preventing or treating osteoporosis.
  • composition is for preventing or treating hypoparathyroidism.
  • composition is for preventing or treating Multiple sclerosis.
  • composition is for preventing or treating Bone disorders.
  • the composition comprises the AC-aa with an AC group comprising 8 carbon atoms and a peptide or a protein.
  • the composition comprises the AC-aa with an AC group comprising 8 carbon atoms and an aa chosen from aromatic amino acid selected from the group consisting of Phenylalanine (Phe), Phenylglycine (PGly), Tryptophane (Trp) and Tyrosine (Tyr) and a peptide or a protein.
  • aromatic amino acid selected from the group consisting of Phenylalanine (Phe), Phenylglycine (PGly), Tryptophane (Trp) and Tyrosine (Tyr) and a peptide or a protein.
  • the composition comprises the AC-aa with an AC group comprising 8 carbon atoms, a peptide or a protein, and a lubricant.
  • the composition comprises the AC-aa with an AC group comprising 8 carbon atoms, a peptide or a protein, and a lubricant which is chosen from the group consisting of magnesium stearate or glyceryl dibehenate.
  • the composition comprises the AC-aa with an AC group comprising 8 carbon atoms, a peptide or a protein and a further permeation enhancer.
  • the composition comprises the AC-aa with an AC group comprising 8 carbon atoms, a peptide or a protein and a further permeation enhancer which is chosen from the group consisting of caprate, in particular sodium caprate, caprylate, in particular sodium caprylate, bile salts, salcaprozate, in particular sodium salcaprozate (SNAC).
  • AC group comprising 8 carbon atoms, a peptide or a protein
  • a further permeation enhancer which is chosen from the group consisting of caprate, in particular sodium caprate, caprylate, in particular sodium caprylate, bile salts, salcaprozate, in particular sodium salcaprozate (SNAC).
  • the composition comprises the AC-aa with an AC group comprising 8 carbon atoms, a peptide or a protein and a pH modifier.
  • the composition comprises the AC-aa with an AC group comprising 8 carbon atoms, a peptide or a protein and a pH modifier which is chosen from the group consisting of sodium carbonate, which formula is Na 2 CO 3 , phosphates, citrates, citric acid, tartarate and tartaric acid.
  • the composition comprises N-octanoyl-Phenylalanine, a peptide or a protein, and a lubricant.
  • the composition comprises N-octanoyl-Phenylalanine, a peptide or a protein, and a lubricant which is chosen from the group consisting of magnesium stearate or glyceryl dibehenate.
  • the composition comprises N-octanoyl-Phenylalanine, a peptide or a protein and a further permeation enhancer.
  • the composition comprises N-octanoyl-Phenylalanine, a peptide or a protein and a further permeation enhancer which is chosen from the group consisting of caprate, in particular sodium caprate, caprylate, in particular sodium caprylate, bile salts, salcaprozate, in particular sodium salcaprozate (SNAC).
  • a further permeation enhancer which is chosen from the group consisting of caprate, in particular sodium caprate, caprylate, in particular sodium caprylate, bile salts, salcaprozate, in particular sodium salcaprozate (SNAC).
  • the composition comprises N-octanoyl-Phenylalanine, a peptide or a protein and a pH modifier.
  • the composition comprises N-octanoyl-Phenylalanine, a peptide or a protein and a pH modifier which is chosen from the group consisting of sodium carbonate, which formula is Na 2 CO 3 , phosphates, citrates, citric acid, tartarate and tartaric acid.
  • a pH modifier which is chosen from the group consisting of sodium carbonate, which formula is Na 2 CO 3 , phosphates, citrates, citric acid, tartarate and tartaric acid.
  • the composition comprises the AC-aa with an AC group comprising 8 carbon atoms, a peptide or a protein, and a lubricant which is magnesium stearate.
  • the composition comprises the AC-aa with an AC group comprising 8 carbon atoms, a peptide or a protein, and a lubricant which is glyceryl dibehenate.
  • the composition comprises the AC-aa with an AC group comprising 8 carbon atoms and an aa chosen from aromatic amino acid selected from the group consisting of Phenylalanine (Phe), Phenylglycine (PGly), Tryptophane (Trp) and Tyrosine (Tyr), a peptide or a protein and a lubricant.
  • Aroma amino acid selected from the group consisting of Phenylalanine (Phe), Phenylglycine (PGly), Tryptophane (Trp) and Tyrosine (Tyr), a peptide or a protein and a lubricant.
  • the composition comprises the AC-aa with an AC group comprising 8 carbon atoms and an aa chosen from aromatic amino acid selected from the group consisting of Phenylalanine (Phe), Phenylglycine (PGly), Tryptophane (Trp) and Tyrosine (Tyr), a peptide or a protein and a lubricant which is magnesium stearate.
  • aromatic amino acid selected from the group consisting of Phenylalanine (Phe), Phenylglycine (PGly), Tryptophane (Trp) and Tyrosine (Tyr), a peptide or a protein and a lubricant which is magnesium stearate.
  • the composition comprises the AC-aa with an AC group comprising 8 carbon atoms and an aa chosen from aromatic amino acid selected from the group consisting of Phenylalanine (Phe), Phenylglycine (PGly), Tryptophane (Trp) and Tyrosine (Tyr), a peptide or a protein and a lubricant which is glyceryl dibehenate.
  • aromatic amino acid selected from the group consisting of Phenylalanine (Phe), Phenylglycine (PGly), Tryptophane (Trp) and Tyrosine (Tyr), a peptide or a protein and a lubricant which is glyceryl dibehenate.
  • the composition comprises the AC-aa with an AC group comprising 8 carbon atoms, a peptide or a protein and a pH modifier.
  • the composition comprises the AC-aa with an AC group comprising 8 carbon atoms, a peptide or a protein and a pH modifier which is sodium carbonate.
  • the composition comprises the AC-aa with an AC group comprising 8 carbon atoms and an aa chosen from aromatic amino acid selected from the group consisting of Phenylalanine (Phe), Phenylglycine (PGly), Tryptophane (Trp) and Tyrosine (Tyr), a peptide or a protein and a pH modifier.
  • aromatic amino acid selected from the group consisting of Phenylalanine (Phe), Phenylglycine (PGly), Tryptophane (Trp) and Tyrosine (Tyr), a peptide or a protein and a pH modifier.
  • the composition comprises the AC-aa with an AC group comprising 8 carbon atoms and an aa chosen from aromatic amino acid selected from the group consisting of Phenylalanine (Phe), Phenylglycine (PGly), Tryptophane (Trp) and Tyrosine (Tyr), a peptide or a protein and a pH modifier which is sodium carbonate.
  • aromatic amino acid selected from the group consisting of Phenylalanine (Phe), Phenylglycine (PGly), Tryptophane (Trp) and Tyrosine (Tyr), a peptide or a protein and a pH modifier which is sodium carbonate.
  • the composition comprises the AC-aa with an AC group comprising 8 carbon atoms, a peptide or a protein, a lubricant and a pH modifier.
  • the composition comprises the AC-aa with an AC group comprising 8 carbon atoms, a peptide or a protein, a lubricant which is magnesium stearate and a pH modifier.
  • the composition comprises the AC-aa with an AC group comprising 8 carbon atoms, a peptide or a protein, a lubricant which is magnesium stearate and a pH modifier which is sodium carbonate.
  • the composition comprises the AC-aa with an AC group comprising 8 carbon atoms, a peptide or a protein, a lubricant which is glyceryl dibehenate and a pH modifier.
  • the composition comprises the AC-aa with an AC group comprising 8 carbon atoms, a peptide or a protein, and a lubricant which is glyceryl dibehenate and a pH modifier which is sodium carbonate.
  • the composition comprises the AC-aa with an AC group comprising 8 carbon atoms and an aa chosen from aromatic amino acid selected from the group consisting of Phenylalanine (Phe), Phenylglycine (PGly), Tryptophane (Trp) and Tyrosine (Tyr), a peptide or a protein, a lubricant and a pH modifier.
  • aromatic amino acid selected from the group consisting of Phenylalanine (Phe), Phenylglycine (PGly), Tryptophane (Trp) and Tyrosine (Tyr), a peptide or a protein, a lubricant and a pH modifier.
  • the composition comprises the AC-aa with an AC group comprising 8 carbon atoms and an aa chosen from aromatic amino acid selected from the group consisting of Phenylalanine (Phe), Phenylglycine (PGly), Tryptophane (Trp) and Tyrosine (Tyr), a peptide or a protein, a lubricant and a pH modifier which is sodium carbonate.
  • aromatic amino acid selected from the group consisting of Phenylalanine (Phe), Phenylglycine (PGly), Tryptophane (Trp) and Tyrosine (Tyr), a peptide or a protein, a lubricant and a pH modifier which is sodium carbonate.
  • the composition comprises the AC-aa with an AC group comprising 8 carbon atoms and an aa chosen from aromatic amino acid selected from the group consisting of Phenylalanine (Phe), Phenylglycine (PGly), Tryptophane (Trp) and Tyrosine (Tyr), a peptide or a protein, a lubricant which is magnesium stearate and a pH modifier.
  • aromatic amino acid selected from the group consisting of Phenylalanine (Phe), Phenylglycine (PGly), Tryptophane (Trp) and Tyrosine (Tyr), a peptide or a protein, a lubricant which is magnesium stearate and a pH modifier.
  • the composition comprises the AC-aa with an AC group comprising 8 carbon atoms and an aa chosen from aromatic amino acid selected from the group consisting of Phenylalanine (Phe), Phenylglycine (PGly), Tryptophane (Trp) and Tyrosine (Tyr), a peptide or a protein, a lubricant which is magnesium stearate and a pH modifier which is sodium carbonate.
  • aromatic amino acid selected from the group consisting of Phenylalanine (Phe), Phenylglycine (PGly), Tryptophane (Trp) and Tyrosine (Tyr), a peptide or a protein, a lubricant which is magnesium stearate and a pH modifier which is sodium carbonate.
  • the composition comprises the AC-aa with an AC group comprising 8 carbon atoms and an aa chosen from aromatic amino acid selected from the group consisting of Phenylalanine (Phe), Phenylglycine (PGly), Tryptophane (Trp) and Tyrosine (Tyr), a peptide or a protein, a lubricant which is glyceryl dibehenate and a pH modifier.
  • aromatic amino acid selected from the group consisting of Phenylalanine (Phe), Phenylglycine (PGly), Tryptophane (Trp) and Tyrosine (Tyr), a peptide or a protein, a lubricant which is glyceryl dibehenate and a pH modifier.
  • the composition comprises the AC-aa with an AC group comprising 8 carbon atoms and an aa chosen from aromatic amino acid selected from the group consisting of Phenylalanine (Phe), Phenylglycine (PGly), Tryptophane (Trp) and Tyrosine (Tyr), a peptide or a protein, a lubricant which is glyceryl dibehenate and a pH modifier which is sodium carbonate.
  • the composition comprises the AC-aa with an AC group comprising 8 carbon atoms, a peptide or a protein, a lubricant and a disintegrant.
  • the composition comprises the AC-aa with an AC group comprising 8 carbon atoms, a peptide or a protein, a lubricant which is magnesium stearate and a disintegrant.
  • the composition comprises the AC-aa with an AC group comprising 8 carbon atoms, a peptide or a protein, a lubricant which is glyceryl dibehenate and a disintegrant.
  • the composition comprises the AC-aa with an AC group comprising 8 carbon atoms and an aa chosen from aromatic amino acid selected from the group consisting of Phenylalanine (Phe), Phenylglycine (PGly), Tryptophane (Trp) and Tyrosine (Tyr), a peptide or a protein, a lubricant and a disintegrant.
  • aromatic amino acid selected from the group consisting of Phenylalanine (Phe), Phenylglycine (PGly), Tryptophane (Trp) and Tyrosine (Tyr), a peptide or a protein, a lubricant and a disintegrant.
  • the composition comprises the AC-aa with an AC group comprising 8 carbon atoms and an aa chosen from aromatic amino acid selected from the group consisting of Phenylalanine (Phe), Phenylglycine (PGly), Tryptophane (Trp) and Tyrosine (Tyr), a peptide or a protein, a lubricant which is magnesium stearate and a disintegrant.
  • aromatic amino acid selected from the group consisting of Phenylalanine (Phe), Phenylglycine (PGly), Tryptophane (Trp) and Tyrosine (Tyr), a peptide or a protein, a lubricant which is magnesium stearate and a disintegrant.
  • the composition comprises the AC-aa with an AC group comprising 8 carbon atoms and an aa chosen from aromatic amino acid selected from the group consisting of Phenylalanine (Phe), Phenylglycine (PGly), Tryptophane (Trp) and Tyrosine (Tyr), a peptide or a protein, a lubricant which is glyceryl dibehenate and a disintegrant.
  • aromatic amino acid selected from the group consisting of Phenylalanine (Phe), Phenylglycine (PGly), Tryptophane (Trp) and Tyrosine (Tyr), a peptide or a protein, a lubricant which is glyceryl dibehenate and a disintegrant.
  • the composition comprises the AC-aa with an AC group comprising 8 carbon atoms, a peptide or a protein, a lubricant, a pH modifier and a disintegrant.
  • the composition comprises the AC-aa with an AC group comprising 8 carbon atoms, a peptide or a protein, a lubricant which is magnesium stearate, a pH modifier and a disintegrant.
  • the composition comprises the AC-aa with an AC group comprising 8 carbon atoms, a peptide or a protein, a lubricant which is magnesium stearate, a pH modifier which is sodium carbonate and a disintegrant.
  • the composition comprises the AC-aa with an AC group comprising 8 carbon atoms, a peptide or a protein, a lubricant which is glyceryl dibehenate, a pH modifier and a disintegrant.
  • the composition comprises the AC-aa with an AC group comprising 8 carbon atoms, a peptide or a protein, and a lubricant which is glyceryl dibehenate, a pH modifier which is sodium carbonate and a disintegrant.
  • the composition comprises the AC-aa with an AC group comprising 8 carbon atoms and an aa chosen from aromatic amino acid selected from the group consisting of Phenylalanine (Phe), Phenylglycine (PGly), Tryptophane (Trp) and Tyrosine (Tyr), a peptide or a protein, a lubricant, a pH modifier and a disintegrant.
  • aromatic amino acid selected from the group consisting of Phenylalanine (Phe), Phenylglycine (PGly), Tryptophane (Trp) and Tyrosine (Tyr), a peptide or a protein, a lubricant, a pH modifier and a disintegrant.
  • the composition comprises the AC-aa with an AC group comprising 8 carbon atoms and an aa chosen from aromatic amino acid selected from the group consisting of Phenylalanine (Phe), Phenylglycine (PGly), Tryptophane (Trp) and Tyrosine (Tyr), a peptide or a protein, a lubricant, a pH modifier which is sodium carbonate and a disintegrant.
  • aromatic amino acid selected from the group consisting of Phenylalanine (Phe), Phenylglycine (PGly), Tryptophane (Trp) and Tyrosine (Tyr), a peptide or a protein, a lubricant, a pH modifier which is sodium carbonate and a disintegrant.
  • the composition comprises the AC-aa with an AC group comprising 8 carbon atoms and an aa chosen from aromatic amino acid selected from the group consisting of Phenylalanine (Phe), Phenylglycine (PGly), Tryptophane (Trp) and Tyrosine (Tyr), a peptide or a protein, a lubricant which is magnesium stearate, a pH modifier and a disintegrant.
  • aromatic amino acid selected from the group consisting of Phenylalanine (Phe), Phenylglycine (PGly), Tryptophane (Trp) and Tyrosine (Tyr), a peptide or a protein, a lubricant which is magnesium stearate, a pH modifier and a disintegrant.
  • the composition comprises AC-aa with an AC group comprising 8 carbon atoms and an aa chosen from aromatic amino acid selected from the group consisting of Phenylalanine (Phe), Phenylglycine (PGly), Tryptophane (Trp) and Tyrosine (Tyr), a peptide or a protein, a lubricant which is magnesium stearate, a pH modifier which is sodium carbonate and a disintegrant.
  • the composition comprises the AC-aa with an AC group comprising 8 carbon atoms and an aa chosen from aromatic amino acid selected from the group consisting of Phenylalanine (Phe), Phenylglycine (PGly), Tryptophane (Trp) and Tyrosine (Tyr), a peptide or a protein, a lubricant which is glyceryl dibehenate, a pH modifier and a disintegrant.
  • aromatic amino acid selected from the group consisting of Phenylalanine (Phe), Phenylglycine (PGly), Tryptophane (Trp) and Tyrosine (Tyr), a peptide or a protein, a lubricant which is glyceryl dibehenate, a pH modifier and a disintegrant.
  • the composition comprises NaPheC8, a peptide or a protein, a lubricant which is glyceryl dibehenate, a pH modifier which is sodium carbonate and a disintegrant.
  • the composition comprises NaPheC8, a peptide or a protein, a lubricant, a pH modifier and a disintegrant.
  • the composition comprises NaPheC8, a peptide or a protein, a lubricant, a pH modifier which is sodium carbonate and a disintegrant.
  • the composition comprises NaPheC8, a peptide or a protein, a lubricant which is magnesium stearate, a pH modifier and a disintegrant.
  • the composition comprises NaPheC8, a peptide or a protein, a lubricant which is magnesium stearate, a pH modifier which is sodium carbonate and a disintegrant.
  • the composition comprises NaPheC8, a peptide or a protein, a lubricant which is glyceryl dibehenate, a pH modifier and a disintegrant.
  • the composition comprises NaPheC8, a peptide or a protein, a lubricant which is glyceryl dibehenate, a pH modifier which is sodium carbonate and a disintegrant.
  • the AC-aa may be obtained by acylation of amino-acids, which may be readily performed using acylation agents known in the art that react with e.g. the free alpha-amino group.
  • the amino acid may be attached to the acid via an N-acylation, i.e. resulting in an amide bond.
  • AC-aa's of the invention may be prepared using the method described in Leone-Bay et al (1995): "N-acylated alpha-amino acids as novel oral delivery agents for proteins", Journal of Medicinal Chemistry, 38(21), 4263-4269 .
  • the solid compositions were prepared by mixing together the AC-aa with the peptide or a protein in appropriate proportions using a mortar and pestle until a sufficient homogeneity was reached. The resulting blend was then introduced manually in Enteric VCaps, size 00 (Capsugel).
  • Capsules were then sealed using the following protocol: 10 ⁇ L of a 50/50 vol/vol mixture of ethanol and water were introduced between the lower part and the upper lid of the capsule using a syringe. The sealing solution was then dried under hot air (45°C) for one minute, leading to an impermeable seal between both parts of the capsule.
  • Example A.1.1 Preparation a NaPheC8 and semaglutide solid composition.
  • composition A.1.1 is prepared according to process A-1 with 15 mg of semaglutide and 395 mg of NaPheC8 per enteric cap.
  • Example B1 Determination of solubilization kinetics of solid NaPheC6 and NaPheC8
  • compacts are prepared in the following manner:
  • PK studies in Beagle dogs were conducted to estimate the exposure and the bioavailability of semaglutide after oral administration of the composition A.1.1 comprising semaglutide and NaPheC8 described in example A.1.1 and after intravenous (iv) administration of semaglutide.
  • a solution of semaglutide (10 ⁇ mol/L) was injected through a catheter, placed in the cephalic vein, to 10 Beagle dogs.
  • Blood was sampled at predefined time up to 72h for oral administration and up to 192h for the iv administartion. Each blood sampling time point was collected in K 2 EDTA tubes containing a cocktail of protease inhibitors stored less than 45min on ice before centrifugation. The centrifugation was performed as follows: 10 min at 1300 G at +4°C. Plasma was collected in two cryotubes with minimum 100 ⁇ L in each one. Cryotubes are stored at -80°C until analysis
  • Plasma concentrations of semaglutide were determined using a LC-MS/MS analysis after protein precipitation extraction.
  • Semaglutide plasma concentration data corrected for actual dose and body weight were subjected to non-compartmental PK analysis using Phoenix WinNonlin V8.2 software (Pharsight, Mountain View, Calif. 94041, USA).
  • Cmax maximum plasma concentration
  • tmax time for maximal concentration
  • AUCinf area under the curve from 0 to infinity
  • Bioavailability (F) was calculated as the fraction absorbed (in %) based on the ratio of dose-normalised AUCinf after oral and iv administration ((AUCinf-oral/dose)/(AUCinf-iv/dose)).
  • Summary statistics of PK parameters were presented as arithmetic mean with corresponding standard deviation (SD).
  • composition A.1.1 comprising semaglutide and NaPheC8 described in Example A.1.1.

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EP21208347.1A 2021-11-15 2021-11-15 Feste zusammensetzungen mit einem peptid oder einem protein und einer acylierten aminosäure Withdrawn EP4180060A1 (de)

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EP21208347.1A EP4180060A1 (de) 2021-11-15 2021-11-15 Feste zusammensetzungen mit einem peptid oder einem protein und einer acylierten aminosäure
EP22818291.1A EP4433093A1 (de) 2021-11-15 2022-11-15 Feste zusammensetzungen mit einem peptid oder einem protein und einer acylierten aminosäure
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WO1995007931A1 (en) 1993-09-17 1995-03-23 Novo Nordisk A/S Acylated insulin
WO2005012347A2 (en) 2003-08-05 2005-02-10 Novo Nordisk A/S Novel insulin derivatives
WO2009063072A2 (en) 2007-11-16 2009-05-22 Novo Nordisk A/S Pharmaceutical compositions containing insulin and an insulinotropic peptide
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